Oriental Foods and Herbs - American Chemical Society

Chapter 3

Targeting Inflammation Using Nutraceuticals Mohamed M. Rafi, Prem N. Yadav, and Il-Kyung Maeng

Downloaded by CORNELL UNIV on September 22, 2016 | http://pubs.acs.org Publication Date: August 5, 2003 | doi: 10.1021/bk-2003-0859.ch003

Department of Food Science, Rutgers, The State University of New Jersey, 65 Dudley Road, New Brunswick,NJ08901-8520

The use of herbal therapy or alternative medicine is becoming an increasingly attractive approach for the treatment of various inflammatory disorders. Significant research efforts in the laboratory and in the clinic are ongoing to understand the critical role of certain nutraceuticals in the regulation of inflammation. This article has reviewed few selected nutraceuticals and their possible mechanism of action in inflammation. The selected nutraceuticals includes, curcumin, resveratrol, epigallocatechin gallate (EGCG) and diarylheptanoids from ginger. In addition, we also discussed our recent work on a diarylheptanoid isolated from Alpinia officinarum, which have potential anti-inflammatory activities and inhibits the expression of COX-2 and iNOS mediated through NF-κΒ activation. This article summarizes possible targets in inflammation and will also provide insights for the development of new anti-inflammatory agents.

Introduction Nutraceuticals have been touted for medical benefits, but little is known about their biological activity. The recent studies have repeatedly shown that many natural products marketed as nutraceuticals, deliver the health benefit in various disease conditions. A wide array of nutraceuticals present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and

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© 2003 American Chemical Society Ho et al.; Oriental Foods and Herbs ACS Symposium Series; American Chemical Society: Washington, DC, 2003.


49 antiinflammatory activities. The majority of naturally occurring phenolics possess tremendous antioxidative and anti-inflammatory activities. Anti inflammatory properties of different nutraceuticals are mediated through the inhibition of production of cytokines (IL-Ιβ, TNF-ct, IL-6, IL-12, IFN-γ), nitric oxide (NO), prostaglandins and leukotrienes. The proinflammatory mediators NO and prostaglandins are produced by actions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), respectively. These inflammatory mediators are soluble, diffusible molecules that act locally at the site of tissue damage and infection, and at more distant sites. The COX-2 and iNOS are important enzymes that mediate most of the inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders (1,2). Since inflammation has been shown as one of the factors causing certain types of cancer, nutraceuticals with potent anti-inflammatory activities are thought to inhibit carcinogenesis. Examples are curcumin, gingerols diarylheptanoids, epigallocatechin gallate (EGCG), and resveratrol, which are known to inhibit various inflammatory mediators. Several studies have shown that eukaryotic transcription factor nuclear factor-kappa Β (NF-κΒ) is involved in regulation of COX-2 and iNOS expression and these phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-κΒ activation. Similarly, the inhibition of proinflammatory cytokine by these nutraceuticals has also been demonstrated in various inflammatory conditions (2,3). The most possible mechanisms underlying inhibition of NF-κΒ activation by aforementioned nutraceuticals is by inhibition of inhibitory kappa Β kinase (IKK), which prevents the degradation of inhibitory-kappa Β (ΙκΒ) and thereby hampers subsequent nuclear translocation of the functionally active subunit of NF-κΒ (4). In this article, we have reviewed the literatures available for the mechanism of action and anti-inflammatory properties of selected nutraceuticals such as curcumin, resveratrol, green tea polyphenols and diarylheptanoids (chemical structures in Figure 1). In addition we have also shown the antiinflammatory properties of a diarylheptanoids from Alpinia galanga and different possible targets in inflammation.

Curcumin Curcumin, an active ingredient of turmeric is commonly used as a spice to give the specific flavor and yellow color to curry (5). Turmeric has also been used for centuries as a traditional medicine to treat inflammatory disorders (6,7). Subsequent studies also demonstrated the anti-inflammatory properties of curcumin (8). Curcumin is known to have a variety of pharmacological effects,

Ho et al.; Oriental Foods and Herbs ACS Symposium Series; American Chemical Society: Washington, DC, 2003.


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Ο

OMe F

ΗΜΡ (7-(4'-hydroxy-3 -methoxyphenyl)-î-phenyïhept-4-en-3-one)

Figure J. Chemical structure of some nutraceuticals.



51 including antitumor, anti-inflammatory, and anti-infectious activities (2). The pleiotropic effects of curcumin on various arms of immune system are well reported. Curcumin has been shown to selectively suppress the stimulation of Τ helper cells 1 (Thl) in various disease conditions (9-11). Treatment of mice with curcumin prevented trinitrobenzene sulfonic acid induced colonic inflammation (3). In this study, authors have clearly shown that curcumin treatment suppressed proinflammatory cytokine mRNA expression and the NF-κΒ activation in colonic mucosa. Subsequent study by Grandjean-Laquerriere et al (12), have shown that curcumin selectively upregulate IL-10 and inhibits the production of TNF-ot, IL-6, in UVB induced keratinocytes. Moreover, Gukovsky et al, (13) have also demonstrated the in vivo anti-inflammatory effect of curcumin in pancreatic inflammation by decreasing the expression of IL-6, TNF-α and iNOS mediated through NF-κΒ and AP-1. It has also been reported that curcumin inhibits TNF-a-induced NF-κΒ activation in human myelomonoblastic leukemia cells and phorbol ester-induced c-Jun/AP-1 activation in mouse fibroblast cells (14,15). The molecular mechanism for NF-κΒ inhibition by curcumin is still not completely understood. However, inhibition of IKK leading to decreased degradation of ΙκΒ has been suggested as most plausible mechanism for action of curcumin (16-19). In Conclusion, all the evidences suggests that anti inflammatory effect of curcumin is mediated through inhibition of transcriptional factors NF-κΒ and AP-1. The anti-inflammatory properties of curcumin have also been well demonstrated in animal models of atherosclerosis, Alzheimer's disease and arthritis (20-23). These properties of curcumin have been shown to be associated with its ability to inhibit the production of proinflammatory cytokines such as TNF-er, IL-1, IL-8, and inducible NO synthase (1,24-26). Although the exact mechanisms involved in the in vivo anti-inflammatory activity of curcumin is not fully defined, it prevents the activation of NF-κΒ, AP-1, and c-Jun kinase (2,27). Recent studies have also shown that curcumin inhibits IL-12 production from macrophages and thereby prevents the differentiation of Thl cells in vitro (28,29). Natarajan and Bright have also demonstrated the beneficial effect of curcumin in Thl cell-mediated inflammatory diseases of the central nervous system in experimental autoimmune encephalomyelitis (//). In addition, the anti-allergic effect of curcumin has also been demonstrated (30). Temkin et al (30) have clearly shown that curcumin significantly suppresses the recombinant human tryptase induced production of IL-6 and IL-8 from human peripheral blood eosinophils.

Resveratrol Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a natural polyphenolic phytoalexin, found in high to moderate quantities in various foods including



52 grapes, peanuts and wine, has been shown to have anti-inflammatory properties. Recent in vitro and a limited number of in vivo studies have documented that physiological concentrations of resveratrol can modulate multiple molecular pathways thought to be associated with the development and progression of cardiovascular disease, cancer and inflammation (31,32). Resveratrol, a representative of hydroxystilbene, has received special attentions since it was known to have a central role in "French Paradox." The anti-inflammatory properties of Resveratrol are shown to be mediated through inhibition of cyclooxygenase (33). It also inhibits arachidonate release (32,34), MAPK activation (35,36), protein kinase C (37), and degranulation of mast cells (38). Previous studies have shown that resveratrol inhibit the translocation of NF-κΒ into the nucleus and control the expression of iNOS (39-42). Moreover, HolmesMcNary et al (42) demonstrated that resveratrol blocks the TNFct induced activation of NF-κΒ, a transcription factor strongly associated with inflammatory diseases and oncogenesis. Manna et al (43) have also demonstrated that resveratrol inhibits TNF-α induced activation of mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), reactive oxygen intermediate generation and lipid peroxidation and thereby blocks the activation of NF-κΒ and AP-1. Thus, it is apparent that NF-κΒ, AP-1 and associated kinases are the most vulnerable targets of resveratrol for its anti-inflammatory activities. In addition, resveratrol possesses structural similarities with estrogenic compounds and have been suggested that it may exert some estrogenic activities through the estrogen receptors (44-46). Effect of estrogen on iNOS is somewhat controversial; some studies have shown that it inhibits nitric oxide production through a classic receptor-mediated pathway (47), while another study has shown that it does not have any effect (48). Recently, Cho et al (49) also confirmed that inhibition of NO by resveratrol is not mediated through estrogen receptor. Reactive oxygen intermediates (ROI) are important mediators of a variety of pathological processes, including inflammation and ischemia/reperfusion injury. Various proinflammatory cytokines and chemokines have been shown in human and animal ischemic brains, suggesting that hypoxia/reoxygenation may induce cytokine production through generation of ROIs. Wang et al (50) have shown the in vitro neuroprotective effect of resveratrol in glial cells. In this study, it is demonstrated that resveratrol significantly inhibited the IL-6 gene expression and protein secretion in mixed glial cultures under hypoxia/hypoglycemia followed by reoxygenation. In addition, the inhibition of TNF-α induced expression of adhesion molecules on endothelial cells and vascular leakage, by resveratrol is also demonstrated (51).


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Green Tea Polyphenols Tea is one of the most popular beverages in the world and various phytochemicals derived from Tea (Camellia sinensis) have drawn a great deal of interest due to beneficial effect on health. Certain epidemiological studies have suggested that regular tea consumption reduces the risk of cancer (52,53). Although tea consists of several components, interest has focused primarily on polyphenols, especially those found in green tea. The green tea polyphenols include (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), (-)epicatechin gallate (ECG) and (-)-epicatechin (EC). Of these, EGCG accounts for >40% of the total polyphenols (54). Following consumption, the polyphenols remain predominantly in their conjugated forms and are primarily excreted intact in the urine (55). These polyphenols have potent antioxidant properties including the scavenging of oxygen radicals and lipid radicals (54). Suganuma et al (56) reported that EGCG inhibits okadaic acid-induced TNFct production and inhibits its gene expression in BALB/3T3 cells. Green tea polyphenols also inhibit NO production and iNOS gene expression in isolated peritoneal macrophages by decreasing NF-κΒ activation (26,57). In a similar in vivo and in vitro study, Yang et al (58) have shown that anti-inflammatory mechanism of green tea polyphenols is mediated at least in part through down-regulation of TNF-α gene expression by blocking NF-κΒ activation. Exposure of skin to UV radiation can cause diverse biological effects, including induction of inflammation, alteration in cutaneous immune cells and impairment of contact hypersensitivity (CHS) responses. The beneficial effects of polyphenolic fractions from green tea in mouse models have been shown to protect against the carcinogenic effects of UVB radiation (52). This suggests that green tea, specifically polyphenols present therein, may be useful against inflammatory dermatoses and immunosuppression caused by solar radiations. Haqqi et al (59) have demonstrated that green tea polyphenolic fractions inhibits collagen induced arthritis by down regulating the expression of COX-2, IFN-γ, and TNF-α in arthritic models. Inflammatory cytokine, interleukin-ΐβ (IL-Ιβ) produced in an arthritic joint by activated synovial cells and infiltrating macrophages, is considered to be one of the most potent catabolic factors in joint diseases (60). IL-Ιβ induces the production of several mediators of cartilage degradation, such as nitric oxide (NO) and matrix metalloproteinases and inhibits the concentration of tissue inhibitor of metalloproteinases in arthritic joints (61-62). Singh et al (63), have shown that EGCG inhibits IL-Ιβ induced expression of iNOS and production of NO in human chondrocytes through the suppression NF-κΒ activation. These findings suggest that green tea polyphenols may be used as a therapeutic agent in inflammatory diseases.


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Diarylheptanoids Diarylheptanoids, which are structurally similar to curcumin are present in certain plants of ginger family (Zingiberaceae) and have been shown to have a strong anti-inflammatory properties. The diarylheptanoids, yakuchinone A (1[4Miydroxy-3'-methoxyphenyl]-7-phenyl-3-heptanone) and yakuchinone Β (1[4'-hydroxy-3'-methoxyphenyl]-7-phenylhept-l-en-3-one), which are present in Alpinia oxyphylla Miquel have been reported to be strong inhibitors of prostaglandin biosynthesis in vitro (64,65). It has been reported that phenolic diarylheptanoids such as yakuchinone Β and demethyl-yakuchinone Β derivative of yakuchinones, inhibit 5-lipoxygenase and cyclooxygenase activity (67,68). Yamazaki et al (69) have shown that a novel phenolic diarylheptanoid derivative, 1 -(3,5-dimethoxy-4-hydroxyphenyl)-7-phenylhept-1 -en-3-one (YPE01), inhibits 5-lipoxygenase activity as well as it suppresses arachidonic acidand 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema in mice. However, it has been reported that nonphenolic diarylheptanoids also have anti inflammatory effects in various experimental models of inflammation in vivo (70,71). Subsequent studies have revealed that yakuchinone A and yakuchinone B, can act as anti-tumor agents, as these compounds inhibits TPA-stimulated superoxide generation and TNF-α production in HL-60 cells (72,73). Diarylheptanoids from Alpinia officinarum Hance (Zingiberaceae), structurally analogous to yakuchinone A and yakuchinone Β also exhibit strong anti-inflammatory effects (74,75). Another structurally related curcuminoid, 7(4'-hydroxy-3'-methoxyphenyl)-l-phenylhept-4-en-3-one (here abbreviated as HMP) from Alpinia Officinarum Hance has been shown to inhibit the prostaglandin synthase activity (68). Recently, we have also isolated this compound from the same plant by bioassay directedfractionationand studied its anti-inflammatory properties. We have shown that treatment of RAW 264.7 cells with HMP (6.25-25 μΜ) significantly inhibited lipopolysaccharide (LPS) stimulated nitric oxide (NO) production (Figure 2). This compound also inhibited the release of LPS induced proinflamatory cytokines, interleukin 1-β (ILl-β) and tumor necrosis factor α (TNF-α) from human PBMCs in vitro (Figure 3). In addition, western blotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that HMP decreased LPSinduced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and mRNA expression in RAW 264.7 cells (Figures 4 and 5). Furthermore, we showed that anti-inflammatory activity is mediated through transcription factor NF-κΒ (Figure 6). Our results suggest that HMP from Alpinia officinarum is a potent anti-inflammatory compound and could be useful for the treatment of inflammation (76).



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Figure 2. Inhibition of nitric oxide production from RA W 264.7 by HMP. RA W 264.7 cells were treated with LPS (0.5 pg/mL) either alone or with different concentrations (25 μΜ-6.25 μΜ) of HMP for 24 hrs and supernatant were collectedfrom each treatment group. The amount of nitrite was measured using Griess reagent. Each bar represents mean ± standard deviation (SD) of 4 replicates of one representative experiment of total five experiments. ^Represents statistical significance of inhibition of LPS stimulated NO production by HMP as compared to LPS alone (*p

Oriental Foods and Herbs - American Chemical Society

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